Methods for the treatment of parkinson&#39;s disease psychosis using pimavanserin

ABSTRACT

Methods for the treatment of Parkinson&#39;s disease psychosis which comprise the administration of pimavanserin.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage filing under 35 U.S.C. §371 ofInternational Application No. PCT/US2013/071792, filed Nov. 26, 2013,which claims priority to U.S. Provisional Application No. 61/730,452,filed Nov. 27, 2012; the contents of each of which are incorporatedherein by reference in their entireties.

FIELD

Provided herein are methods for the treatment of Parkinson's diseasepsychosis (hereafter, “PDP”) which comprise the administration ofpimavanserin.

BACKGROUND

Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in thefunctioning of the mammalian body. In the central nervous system, 5-HTis an important neurotransmitter and neuromodulator that is implicatedin such diverse behaviors and responses as sleeping, eating, locomotion,perceiving pain, learning and memory, sexual behavior, controlling bodytemperature and blood pressure. In the spinal column, serotonin plays animportant role in the control systems of the afferent peripheralnociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)). Peripheralfunctions in the cardiovascular, hematological and gastrointestinalsystems have also been ascribed to 5-HT. 5-HT has been found to mediatea variety of contractile, secretory, and electrophysiologic effectsincluding vascular and nonvascular smooth muscle contraction, andplatelet aggregation. (Fuller, Biology of Serotonergic Transmission,1982; Boullin, Serotonin In Mental Abnormalities 1:316 (1978); Barchas,et al., Serotonin and Behavior, (1973)). The 5-HT2A receptor subtype(also referred to as subclass) is widely yet discretely expressed in thehuman brain, including many cortical, limbic, and forebrain regionspostulated to be involved in the modulation of higher cognitive andaffective functions. This receptor subtype is also expressed on matureplatelets where it mediates, in part, platelet aggregation, one of theinitial steps in the process of vascular thrombosis.

Given the broad distribution of serotonin within the body, it isunderstandable that tremendous interest in drugs that affectserotonergic systems exists (Gershon, et al., The Peripheral Actions of5-Hydroxytryptamine, 246 (1989); Saxena, et al., J. CardiovascularPharmacol. 15: Supp. 7 (1990)). Serotonin receptors are members of alarge human gene family of membrane-spanning proteins that function astransducers of intercellular communication. They exist on the surface ofvarious cell types, including neurons and platelets, where, upon theiractivation by either their endogenous ligand serotonin or exogenouslyadministered drugs, they change their conformational structure andsubsequently interact with downstream mediators of cellular signaling.Many of these receptors, including the 5-HT2A subclass, are G-proteincoupled receptors (GPCRs) that signal by activating guanine nucleotidebinding proteins (G-proteins), resulting in the generation, orinhibition of, second messenger molecules such as cyclic AMP, inositolphosphates, and diacylglycerol. These second messengers then modulatethe function of a variety of intracellular enzymes, including kinasesand ion channels, which ultimately affect cellular excitability andfunction.

At least 15 genetically distinct 5-HT receptor subtypes have beenidentified and assigned to one of seven families (5-HT1-7). Each subtypedisplays a unique distribution, preference for various ligands, andfunctional correlate(s).

Serotonin may be an important component in various types of pathologicalconditions such as certain psychiatric disorders (depression,aggressiveness, panic attacks, obsessive compulsive disorders,psychosis, schizophrenia, suicidal tendency), certain neurodegenerativedisorders (Alzheimer-type dementia, Parkinsonism, Huntington's chorea),anorexia, bulimia, disorders associated with alcoholism, cerebralvascular accidents, and migraine (Meltzer, Neuropsychopharmacology,21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152(1999); Glennon, Neurosci. Biobehavioral Rev., 14:35 (1990)).

Given the broad distribution of serotonin within the body and its rolein a wide range of physiological and pathological processes, it isunderstandable that there is tremendous interest in drugs that affectserotonergic systems (Gershon, et al., The Peripheral Actions of5-Hydroxytryptamine, 246 (1989); Saxena, et al., J. CardiovascularPharmacol. 15: Supp. 7 (1990)).

The effects of serotonin are mediated by at least 15 geneticallydistinct 5-HT receptor subtypes have been identified and assigned to oneof seven families (5-HT1-7). Each subtype displays a uniquedistribution, preference for various ligands, and functionalcorrelate(s). Serotonin receptors are members of a large human genefamily of membrane-spanning proteins that function as transducers ofintercellular communication. They exist on the surface of various celltypes, including neurons and platelets, where, upon their activation byeither their endogenous ligand serotonin or exogenously administereddrugs, they change their conformational structure and subsequentlyinteract with downstream mediators of cellular signaling. Many of thesereceptors, including the 5-HT2A subclass, are G-protein coupledreceptors (GPCRs) that signal by activating guanine nucleotide bindingproteins (G-proteins), resulting in the generation, or inhibition of,second messenger molecules such as cyclic AMP, inositol phosphates, anddiacylglycerol. These second messengers then modulate the function of avariety of intracellular enzymes, including kinases and ion channels,which ultimately affect cellular excitability and function.

The 5-HT2A receptor subtype (also referred to as subclass) is widely yetdiscretely expressed in the human brain, including many cortical,limbic, and forebrain regions postulated to be involved in themodulation of higher cognitive and affective functions. This receptorsubtype is also expressed on mature platelets where it mediates, inpart, platelet aggregation, one of the initial steps in the process ofvascular thrombosis. Recent evidence strongly implicates the 5-HT2receptor subtype in the etiology of such medical conditions ashypertension, thrombosis, migraine, vasospasm, ischemia, depression,anxiety, psychosis, schizophrenia, sleep disorders and appetitedisorders.

Parkinson's disease is a common neurodegenerative disease which affectsa significant part of the elderly population. PDP is a particularlydevastating neuropsychiatric complication of Parkinson's disease thataffects a majority of the patient population with advanced disease.Current treatment primarily involves pharmacotherapy with a class ofdrugs known as antipsychotics. Antipsychotics have been shown toeffective in ameliorating positive symptoms in PDP (e.g., hallucinationsand delusions), yet they frequently do not improve negative symptoms(e.g., social and emotional withdrawal, apathy, and poverty of speech).

Currently, antipsychotics are prescribed to treat psychotic symptoms inPDP patients but the use of these compounds is limited by their sideeffect profiles. Nearly all of the “typical” or older generationcompounds have significant adverse effects on human motor function.These “extrapyramidal” side effects, so termed due to their effects onmodulatory human motor systems, can be both acute (e.g., dystonicreactions, a potentially life threatening but rare neuroleptic malignantsyndrome) and chronic (e.g., akathisias, tremors, and tardivedyskinesia). Drug development efforts have, therefore, focused on newer“atypical” agents free of some of these adverse effects. However,atypical agents also have the potential for serious side effectsincluding increased risk of stroke, abnormal shifts in sleep patterns,extreme tiredness and weakness, metabolic disorders (includinghyperglycemia and diabetes), and weight gain. One of the most commonreasons for noncompliance and discontinued use of antipsychoticmedication is weight gain. Non-compliance can lead to increasedhospitalization and health care costs.

Antipsychotic drugs have been shown to interact with a large number ofcentral monoaminergic neurotransmitter receptors, includingdopaminergic, serotonergic, adrenergic, muscarinic, and histaminergicreceptors. It is likely that the therapeutic and adverse effects ofthese drugs are mediated by distinct receptor subtypes. The high degreeof genetic and pharmacological homology between these receptor subtypeshas hampered the development of subtype-selective compounds, as well asthe determination of the normal physiologic or pathophysiologic role ofany particular receptor subtype. Thus there is a need to develop drugsthat are selective for individual receptor classes and subclassesamongst monoaminergic neurotransmitter receptors.

The prevailing theory for the mechanism of action of antipsychotic drugsinvolves antagonism of dopamine D2 receptors. Unfortunately, it islikely that antagonism of dopamine D2 receptors also mediates theextrapyramidal side effects as well as some additional undesired effectsof antipsychotic therapies such as a worsening of depression symptoms,anhedonia and impairment of cognitive processes. Antagonism of 5-HT2Areceptors is an alternate molecular mechanism for drugs withantipsychotic efficacy, possibly through antagonism of heightened orexaggerated signal transduction through serotonergic systems. 5-HT2Aantagonists are therefore good candidates for treating psychosis withoutextrapyramidal side effects or other undesired effects associated withblockade of dopamine D₂ receptors.

Traditionally, GPCRS such as the 5-HT2A receptor have been assumed toexist in a quiescent state unless activated by the binding of an agonist(a drug that activates a receptor). It is now appreciated that many, ifnot most, of the GPCR monoamine receptors, including serotoninreceptors, can exist in a partially activated state in the absence oftheir endogenous agonists. This increased basal activity (constitutiveactivity) can be inhibited by compounds called inverse agonists. Bothagonists and inverse agonists possess intrinsic activity at a receptor,in that they alone can activate or inactivate these molecules,respectively. In contrast, classic or neutral antagonists competeagainst agonists and inverse agonists for access to the receptor, but donot possess the intrinsic ability to inhibit elevated basal orconstitutive receptor responses.

SUMMARY

Provided herein are methods for the treatment of Parkinson's diseasepsychosis (hereafter, “PDP”) which comprise the administration ofpimavanserin. Also provided herein are methods of treating Parkinson'sdisease psychosis in a patient as described above, wherein pimavanserinis administered in alternation or in combination with ananti-Parkinson's agent.

Another embodiment described herein includes a method of inducing earlyor rapid onset of an antipsychotic effect, comprising administeringpimavanserin to a subject suffering from PDP.

Also provided herein are methods for the improvement of sleep in aParkinson's disease patient, comprising the oral administration ofpimavanserin, or a pharmaceutically acceptable salt thereof. In oneembodiment, the improvement of sleep is measured on the Scales forOutcomes in Parkinson's Disease—Sleep scale.

Also provided herein is a method for reducing caregiver burden duringthe treatment of Parkinson's disease psychosis by the administration ofpimavanserin to a PDP patient.

Also provided herein is a method for excluding from a clinical studyParkinson's disease psychosis patients with a high likelihood forplacebo response, the method comprising screening a group of Parkinson'sdisease psychosis patients by administering one day to two weeks ofsocial interaction therapy designed for Parkinson's disease psychosispatients, wherein patients who respond sufficiently to the socialinteraction therapy are excluded from a subsequent clinical study.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the PDP patient pathway from screening to open-labeltreatment in the Phase III clinical trial.

FIG. 2 is a graph depicting antipsychotic efficacy of pimavanserin inPDP patients on the Scale for the Assessment of Positive Symptoms(SAPS-PD).

FIG. 3 is a graph depicting improvement in nighttime sleep and daytimewakefulness of PDP patients treated with pimavanserin.

FIG. 4 is a graph depicting reduction in caregiver burden as a result oftreatment of PDP patients with pimavanserin.

DETAILED DESCRIPTION

Provided herein are methods for the treatment of Parkinson's diseasepsychosis which comprise the administration of pimavanserin. Alsoprovided herein are methods of treating Parkinson's disease psychosis ina patient as described above, wherein pimavanserin is administered inalternation or in combination with an anti-Parkinson's agent.

Another embodiment described herein includes a method of inducing arapid or early onset of an antipsychotic effect in a patient sufferingfrom PDP, comprising administering pimavanserin to a subject sufferingfrom PDP such that there is a rapid or early onset of an antipsychoticeffect. Rapid or early onset of an antipsychotic effect is measured ascompared to conventional therapies for PDP, such as the administrationof an antipsychotic agent. Exemplary agents used for the treatment ofPDP include, but are not limited to, clozapine, olanzapine,aripiprazole, ziprasidone, quetiapine, cholinesterase inhibitors,tacrine, donepezil, and rivastigmine.

In some embodiments, administration of pimavanserin results in an earlyonset of one or more efficacious effects. In some embodiments, theefficacious effect is the reduction of psychotic symptoms. In oneembodiment, the efficacious effect is measured by the Scale for theAssessment of Positive Symptoms (SAPS). SAPS is published by TheMovement Disorder Society at www.movementdisorders.org (last visitedNov. 13, 2012); see also Fernandez et al., Movement Disorders, 2008,23(4): 484-500.

In one embodiment, the efficacious effect is measured by the combinedscore for the modified 9-item Hallucinations and Delusions domains ofthe Scale for the Assessment of Positive Symptoms for Parkinson'sdisease psychosis (SAPS-PD). See Voss et al., Parkinsonism & Relat.Disord., 2013, 19(3): 295-99 (e-publication was available on Dec. 1,2012 at http://www.ncbi.nlm.nih.gov/pubmed/23211417). The SAPS-PD scaleis designed to enhance sensitivity for assessing PDP and reduce noise orthe placebo effect in clinical trials.

SAPS-PD includes the following 9 items from the hallucinations anddelusions SAPS scale: auditory hallucinations, voices conversing,somatic or tactile hallucinations, visual hallucinations, global ratingof severity of hallucinations, persecutory delusions, delusions ofjealousy, delusions of reference, and global rating of severity ofdelusions. Each item is assessed according to standard SAPS methodology.See Fernandez et al., Movement Disorders, 2008, 23(4): 484-500.

In another embodiment, the efficacious effect is measured by changes inthe Clinical Global Impression Scale (CGI), with emphasis on severity(CGI-S) and improvement (CGI I) of psychosis. See Busner & Targum,Psychiatry, 2007, vol. 4(7): 28-37.

All combinations of the above measurements of efficacy are part of thedisclosure provided herein.

In some embodiments, the early or rapid onset of efficacious activity isdemonstrated by a clinically relevant therapeutic effect being achievedgreater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%,110%, 130%, 150%, 200%, 300%, 400%, or 500% faster than whenpimavanserin is administered alone at an efficacious dose. In someembodiments, the early or rapid onset of efficacious activity isdemonstrated by a greater percentage of patients experiencing anefficacious effect after a specified period of time as compared toplacebo or lack of treatment. In various embodiments, the percentage ofpatients experiencing an efficacious effect is increased by greater thanabout 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 130%, 150%,200%, 300%, 400%, or 500%. In some embodiments, the specified period oftime is two weeks, four weeks or six weeks. In one embodiment, thespecified period of time is six weeks.

Also provided herein is a method for the improvement of sleep in aParkinson's disease patient, comprising the oral administration ofpimavanserin, or a pharmaceutically acceptable salt thereof. In oneembodiment, the improvement of sleep is measured on the Scales forOutcomes in Parkinson's Disease—Sleep scale. See Martinez-Martin et al.Movement Disorders, 2008, vol. 23(12): 1681-1688; Marinus et al., SLEEP,2003, vol. 26(8): 1049-54.

In one embodiment, provided herein is a method for the improvement ofsleep in a Parkinson's disease patient, comprising the oraladministration of pimavanserin, or a pharmaceutically acceptable saltthereof, to the patient in a daily dose of about 40 mg, wherein theimprovement of sleep is measured on the Scales for Outcomes inParkinson's Disease—sleep scale (SCOPA-sleep). In one embodiment, themethod is for the improvement of nighttime sleep as measured ordetermined by the SCOPA-sleep scale (nighttime sleep problems). Inanother embodiment, the method is for the improvement of daytimewakefulness as measured or determined by the SCOPA-sleep scale (daytimesleepiness). Other scales may be used to evaluate nighttime sleep anddaytime wakefulness, as described in Marinus et al., SLEEP, 2003, vol.26(8): 1049-54.

Also provided herein is a method for reducing caregiver burden duringthe treatment of Parkinson's disease psychosis by the administration ofpimavanserin to a PDP patient. In some embodiments, the reduction incaregiver burden is measured on the Caregiver Burden Scale. In oneembodiment, provided herein is a method for reducing caregiver burdenduring the treatment of Parkinson's disease psychosis, comprising theoral administration of pimavanserin, or a pharmaceutically acceptablesalt thereof, to a Parkinson's disease patient in a daily dose of about40 mg, wherein the reduction in caregiver burden is measured on theCaregiver Burden Scale. See Zarit et al, 1980, The Gerontologist, vol.20: 649-655. The Caregiver Burden Scale is completed by the subject'sattending caregiver. It allows assessment of the potential forpimavanserin to ameliorate the stress on caregivers. Thisself-administered 22-item questionnaire is commonly used in caregiversof the dementia patient population, most specifically in caregivers ofsubjects with Alzheimer's disease. Nonetheless, it has been reported tohave high reliability in PD. See Aarsland et al., J. Neurol. Neurosurg.Psychiatry, 1999, vol. 67(4): 492-496.

Also provided herein are methods of treating Parkinson's diseasepsychosis in a patient as described above, wherein pimavanserin isadministered in alternation or in combination with an anti-Parkinson'sagent. In some embodiments, the patient is concurrently treated with ananti-Parkinson's agent. In some embodiments, the anti-Parkinson's agentis selected from the group consisting of levodopa, carbidopa,carbidopa-levodopa, benserazide-levodopa, benztropine, trihexylphenidyl,amantadine, pramipexole, selegiline, rasagiline, entacapone, tolcapone,ropinirole, and apomorphine.

Also provided herein is a method for excluding from a clinical studyParkinson's disease psychosis patients with a high likelihood forplacebo response, the method comprising screening a group of Parkinson'sdisease psychosis patients by administering one day to two weeks ofsocial interaction therapy designed for Parkinson's disease psychosispatients, wherein patients who respond sufficiently to the socialinteraction therapy are excluded from a subsequent clinical study.

In some embodiments, the social interaction therapy designed forParkinson's disease psychosis patients is a brief psycho-social therapy(BPST) designed as per current supportive care guidelines and modifiedfor PD (BPST-PD). Patients who responded sufficiently to thisnon-pharmacologic social interaction therapy (i.e., who no longer meetstudy entry criteria) are excluded from the clinical study, whereaspatients who do not materially improve during this phase have the optionof entering the treatment period of the clinical study early.

In some embodiments, BPST-PD used is as described in Example 7, infra.

Also provided herein is a method for conducting a clinical study in agroup of Parkinson's disease psychosis patients, the method comprising:

-   -   (i) screening a group of Parkinson's disease psychosis patients        by administering one day to two weeks of social interaction        therapy designed for Parkinson's disease psychosis patients,        wherein patients who respond to the social interaction therapy        are excluded from the clinical study;    -   (ii) dividing the patients who were not excluded into a        treatment group and a placebo group;    -   (iii) administering a drug to the treatment group for a        designated period of time; and    -   (iv) evaluating the results of the clinical study by comparing        the treatment group to the placebo group.

In one embodiment, pimavanserin is administered to the patients in thetreatment group.

Compound

Pimavanserin, which is also known asN-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide,N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N′-[[4-(2-methylpropoxy)phenyl]methyl]-urea,1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea,or ACP-103 has the structure of Formula (I):

Pimavanserin and methods for its use are described in U.S. Pat. Nos.7,601,740; 7,659,285; 7,713,995; 7,732,462; 7,994,193 and 8,008,323, theentirety of each of which is hereby incorporated by reference.Pimavanserin can be obtained in a number of salt and crystalline forms.Exemplary pharmaceutically acceptable salts include the tartrate,hemi-tartrate, citrate, fumarate, maleate, malate, phosphate, succinate,sulphate, and edisylate (ethanedisulfonate) salts. Pimavanserin saltsincluding the aforementioned ions, among others, are described in U.S.Patent Publication No. 2006-0111399, filed Sep. 26, 2005, the entiretyof which is incorporated herein by reference. In an embodiment providedherein, pimavanserin is the tartrate salt of pimavanserin. Severalcrystalline forms of the tartrate salt of pimavanserin have beendescribed in U.S. Patent Publication No. 2006-0106063, filed Sep. 26,2006, the entirety of which is incorporated herein by reference. Seealso U.S. Pat. Nos. 7,732,615; 7,795,547; 7,790,899; 7,868,176, theentirety of each of which is incorporated herein by reference. In anembodiment provided herein, pimavanserin is the crystalline form of thetartrate salt of pimavanserin Form A. In another embodiment,pimavanserin is the crystalline form of the tartrate salt ofpimavanserin Form C. Pimavanserin (including, for example, the tartratesalt) may be formulated into tablets, such as is described in U.S.Patent Publication Nos. 2007-0260064, filed May 15, 2007 and2007-0264330, filed May 15, 2007, each of which are incorporated hereinby reference in their entireties. Metabolites of pimavanserin aredescribed in U.S. Patent Publication No. 2009/0082342, the entirety ofwhich is hereby incorporated by reference.

The pharmacological activity of pimavanserin has been previouslyreported. See U.S. Patent Publication Nos. 2004/0213816 and2009/0053329, the entirety of each of which is hereby incorporated byreference. Pimavanserin is active in a number of models thought to bepredictive of antipsychotic activity such as DOI((±)-2,5-dimethoxy-4-iodoamphetamine, a serotonin agonist) induced headtwitches in the rat and attenuation of hyperactivity in mice induced bythe N-methyl-D-aspartate antagonist MK-801. The compound was effectivein these models at oral doses of 3 and 10 mg/kg. In a rat model ofdeficits in sensory motor gating similar to those exhibited byschizophrenics, pimavanserin at doses of 1 and 3 mg/kg SC potentlyreversed the gating deficit induced by DOI. Pimavanserin also failed todisrupt learning of a simple auto-shaped response in mice atintraperitoneal doses up to 32 mg/kg. The pharmacological profile ofpimavanserin suggests it will be effective as an antipsychotic agentwithout the side effects common to other compounds in this class. Thus,pimavanserin will have antipsychotic activity when used to treatschizophrenic subjects.

DEFINITIONS

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism, suchas a human, to which it is administered and does not abrogate thebiological activity and properties of the compound. In some embodiments,the salt is an acid addition salt of the compound. Pharmaceutical saltscan be obtained by reacting a compound with inorganic acids such ashydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuricacid, nitric acid, phosphoric acid and the like. Pharmaceutical saltscan also be obtained by reacting a compound with an organic acid such asaliphatic or aromatic carboxylic or sulfonic acids, for example acetic,succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic,methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic ornaphthalenesulfonic acid. Pharmaceutical salts can also be obtained byreacting a compound with a base to form a salt such as an ammonium salt,an alkali metal salt, such as a sodium or a potassium salt, an alkalineearth metal salt, such as a calcium or a magnesium salt, a salt oforganic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine,triethanolamine, ethylenediamine, and salts with amino acids such asarginine, lysine, and the like.

The term “carrier” defines a chemical compound that facilitates theincorporation of a compound into cells or tissues. For example dimethylsulfoxide (DMSO) is a commonly utilized carrier as it facilitates theuptake of many organic compounds into the cells or tissues of anorganism.

The term “diluent” defines chemical compounds diluted in water that willdissolve the compound of interest as well as stabilize the biologicallyactive form of the compound. Salts dissolved in buffered solutions areutilized as diluents in the art. One commonly used buffered solution isphosphate buffered saline because it mimics the salt conditions of humanblood. Since buffer salts can control the pH of a solution at lowconcentrations, a buffered diluent rarely modifies the biologicalactivity of a compound.

The term “physiologically acceptable” defines a carrier or diluent thatdoes not abrogate the biological activity and properties of thecompound.

The terms “improvement,” “improved” and “improves” as used herein withrespect to the clinical setting refer to a clinically relevant effectbeing achieved greater than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 200%,300%, 400%, or 500% when compared to baseline after a specified periodof time. In some embodiments, the improvement refers to improvedefficacious effect in a single patient after the administration ofpimavanserin as compared to baseline (i.e., prior to the administrationof pimavanserin). In other embodiments, the improvement refers to thedemonstration of efficacy by a greater percentage of patientsexperiencing an efficacious effect after a specified period of time ascompared to placebo or lack of treatment. In various embodiments, thepercentage of patients experiencing an efficacious effect is increasedby greater than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 200%, 300%, 400%,or 500% when compared to placebo or lack of treatment. In someembodiments, the specified period of time is about two weeks, four weeksor six weeks. In one embodiment, the specified period of time is sixweeks.

The term “nighttime sleep” refers to sleep at night. Improvement ofnighttime sleep refers to improvement of patient problems with sleepingat night, including but not limited to the ability to fall asleep andthe ability to sleep through the night without waking Improvement ofnighttime sleep may be measured or determined by use of the SCOPA-sleepscale (nighttime sleep problems). Other scales may be used to evaluatenighttime sleep, as described in Marinus et al., SLEEP, 2003, vol.26(8): 1049-54.

The term “daytime wakefulness” refers to the ability to remain awakeduring daylight hours. Improvement of daytime wakefulness refers toreduced episodes of dozing off and improvement in the ability to stayawake during daylight hours. Improvement of daytime wakefulness may bemeasured or determined by use of the SCOPA-sleep scale (daytimesleepiness). Other scales may be used to evaluate daytime wakefulness,as described in Marinus et al., SLEEP, 2003, vol. 26(8): 1049-54.

Pharmaceutical Compositions

Techniques for formulation and administration of the compositionsdescribed herein may be found in “Remington's Pharmaceutical Sciences,”Mack Publishing Co., Easton, Pa., 18th edition, 1990.

Suitable routes of administration may, for example, include oral,rectal, transmucosal, topical, or intestinal administration; parenteraldelivery, including intramuscular, subcutaneous, intravenous,intramedullary injections, as well as intrathecal, directintraventricular, intraperitoneal, intranasal, or intraocularinjections. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills, transdermal (including electrotransport) patches, and thelike, for prolonged and/or timed, pulsed administration at apredetermined rate.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or tableting processes.

Pharmaceutical compositions for use as described herein thus may beformulated in conventional manner using one or more physiologicallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically. Proper formulation is dependent upon theroute of administration chosen. Any of the well-known techniques,carriers, and excipients may be used as suitable and as understood inthe art; e.g., in Remington's Pharmaceutical Sciences, above.

Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, mannitol, lactose,lecithin, albumin, sodium glutamate, cysteine hydrochloride, and thelike. In addition, if desired, the injectable pharmaceuticalcompositions may contain minor amounts of nontoxic auxiliary substances,such as wetting agents, pH buffering agents, and the like.Physiologically compatible buffers include, but are not limited to,Hank's solution, Ringer's solution, or physiological saline buffer. Ifdesired, absorption enhancing preparations (for example, liposomes), maybe utilized.

For transmucosal administration, penetrants appropriate to the barrierto be permeated may be used in the formulation.

Pharmaceutical formulations for parenteral administration, e.g., bybolus injection or continuous infusion, include aqueous solutions of theactive compounds in water-soluble form. Additionally, suspensions of theactive compounds may be prepared as appropriate oily injectionsuspensions. Suitable lipophilic solvents or vehicles include fatty oilssuch as sesame oil, or other organic oils such as soybean, grapefruit oralmond oils, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. Aqueous injection suspensions may containsubstances which increase the viscosity of the suspension, such assodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents that increasethe solubility of the compounds to allow for the preparation of highlyconcentrated solutions. Formulations for injection may be presented inunit dosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compounds with solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate. Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

Further disclosed herein are various pharmaceutical compositions wellknown in the pharmaceutical art for uses that include intraocular,intranasal, and intraauricular delivery. Suitable penetrants for theseuses are generally known in the art. Pharmaceutical compositions forintraocular delivery include aqueous ophthalmic solutions of the activecompounds in water-soluble form, such as eyedrops, or in gellan gum(Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayeret al., Ophthalmologica, 210(2):101-3 (1996)); ophthalmic ointments;ophthalmic suspensions, such as microparticulates, drug-containing smallpolymeric particles that are suspended in a liquid carrier medium(Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)), lipid-solubleformulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)),and microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); andocular inserts. All of the above-mentioned references, are incorporatedherein by reference in their entireties. Such suitable pharmaceuticalformulations are most often and preferably formulated to be sterile,isotonic and buffered for stability and comfort. Pharmaceuticalcompositions for intranasal delivery may also include drops and spraysoften prepared to simulate in many respects nasal secretions to ensuremaintenance of normal ciliary action. As disclosed in Remington'sPharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.(1990), which is incorporated herein by reference in its entirety, andwell-known to those skilled in the art, suitable formulations are mostoften and preferably isotonic, slightly buffered to maintain a pH of 5.5to 6.5, and most often and preferably include antimicrobialpreservatives and appropriate drug stabilizers. Pharmaceuticalformulations for intraauricular delivery include suspensions andointments for topical application in the ear. Common solvents for suchaural formulations include glycerin and water.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

EXAMPLES Example 1 Preparation of Pimavanserin

Pimavanserin may be synthesized by methods described below, or bymodification of these methods. Ways of modifying the methodologyinclude, among others, modification in temperature, solvent, reagents,etc. An exemplary method of preparing pimavanserin is as follows.

a) Preparation of

The reaction step was performed in three batches, which were eachmanufactured on the same scale as described below and the resultingproducts combined for further use in the next step. N-Methylpiperidone(33.0 kg) and 4-fluorobenzylamine (35.4 kg) were dissolved in methanol(220.1 kg) at 15-19° C. (exothermic dissolution), and a suspension of 5%palladium on charcoal (1.2 kg) in methanol (16.8 kg) was added undernitrogen and the line rinsed with methanol (5.6 kg). The bulk was heatedto 23-27° C. and hydrogenated at the same temperature and ˜5 bar untilthe hydrogen absorption stopped (˜12 h). The residual starting materialwas checked by GC, and the bulk was clarified on a Lens filter equippedwith a thin Celtrox pad and 2×G92 filter papers. The line was rinsedwith methanol (9.8 kg). The solvent was distilled under reduced pressure(265-60 mbar; 35-40° C.) and the oily residue was purified by fractionaldistillation under vacuum at ˜135-140° C. at 8-0.5 mbar. Impurefractions of the three batches were combined and redistilled.

Total yield (combined three batches and redistilled fractions): 147.4 kg(78.1%).

b) Preparation of

The reaction step was performed in two batches. 4-Hydroxybenzaldehyde(141 kg) was dissolved in dimethylformamide (335 kg) at 15-25° C., thensolid potassium carbonate (323 kg) and potassium iodide (19 kg) wereadded portion wise at <30° C. and the suspension was heated up to 78-82°C. The temperature of the condenser was fixed to −10° C. andisobutylbromide (317 kg) was added to the suspension over 4 h 50 min at78-82° C. At the end of the addition, the mixture was stirred for 2 h at78-82° C. and residual starting material was checked by HPLC. Thesuspension was cooled to 20-30° C., diluted with 100% ethanol (501 kg,denatured with isopropanol), stirred for 15 min at 20-30° C. andcentrifuged (3 loadings) to remove the excess of carbonate and potassiumbromide. The line and the cake were washed with 100% ethanol (2×32kg/loading). The solution is used as such in the next step.

c) Preparation of

To the aldehyde solution resulting from Step b, 50% hydroxylamine inwater (115 kg) was added at room temperature over ˜0.5 h (the additionis slightly exothermic), the line washed with ethanol (8 kg), then thebulk was heated up to 73-77° C. and stirred at this temperature for 2 h.The bulk was concentrated under reduced pressure (250-120 mbar, 45-55°C.) to ˜850 L, the residue quenched with water (951 kg) at 45-55° C. andthe residual ethanol distilled under vacuum (270-150 mbar, 45-55° C.,residual volume=1466 L). The bulk was diluted with petrol ether 60-90(557 kg) and heated at reflux (˜60° C.) to reach complete dissolution(˜20 min, visual check). The solution was cooled down to 8-12° C.(crystallization occurs at T=˜27° C.) over ˜5.5 h. After 0.5 h stirringat 10° C., the mixture was cooled to 0-5° C. and stirred at thistemperature for 2 h. The bulk was centrifuged (3 loadings) and the cakewashed with petrol ether (2×23 kg/loading), then dried under reducedpressure at 40° C. to afford the crude oxime (212 kg).

Recrystallization:

The crude product (212 kg) was dissolved in hexane (642 kg) at 15-25° C.and the suspension heated up to ˜62° C. Charcoal (6 kg) in hexane (26kg) was added and the suspension was stirred for 0.5 h. After filtration(the filter was washed with 33 kg hexane), the solution was cooled tocrystallisation temperature (˜55° C.), and the mixture was stirred for 1h at this temperature. The suspension was cooled to 10-15° C. Afterstirring for ˜2 h at that temperature, the bulk was centrifuged (3loadings) and the cake washed with cold hexane (2×13 kg/loading), thendried under reduced pressure at 40° C.

Yield oxime: 196 kg (87.9% over the two steps)

d) Preparation of

The oxime (198 kg) from Step c was dissolved in ethanol (1148 kg,denatured with isopropanol). Raney nickel catalyst (29 kg) was washedwith ethanol (692 kg) until the water content by Karl Fischer was below300 ppm, then the anhydrous Raney-Nickel was added under nitrogen to theoxime solution, the line washed with ethanol (62 kg) and the suspensioncooled down to −10° C. Ammonia gas (229 kg) was added under vacuum over˜6 h (the addition is exothermic). Then the suspension was heated to 49°C. The internal pressure increased to ˜3 bar. The bulk was hydrogenatedat 49° C. and 4 bar until the hydrogen absorption stopped (˜9 h) and theend of reaction was checked by HPLC. The suspension was cooled to 13°C., the excess of ammonia was removed, and the bulk clarified byfiltration over Celtrox (4 kg). The line was washed with ethanol (317kg). The solvent was distilled under reduced pressure (150-10 mbar,40-50° C.) and the residue dissolved in toluene (780 kg) at ˜40° C. Thesolution was transferred to a new reactor (previous reactor washed with57 kg toluene), and cooled to 22° C. Acetic acid (60 kg) was slowlyadded (exothermic reaction) at 22° C. and the bulk heated during 20 minto ˜95° C. until complete dissolution was reached. The solution wascooled rapidly to 80° C. and seeded with amino acetate product (50 g).The suspension was stirred at the crystallization temperature for 30min, cooled to 10° C. and stirred for ˜1 h at this temperature. The bulkwas centrifuged (3 loadings) and the cake washed with cold toluene (2×48L/loading) and finally dried under vacuum at (9-16 mbar) at ˜50° C. for28 h.

Yield: 207 kg (83.6%)

e) Preparation of

A solution of the aminoacetate (269 kg) from Step d in water (431 kg)was basified with 30% sodium hydroxide solution (305 kg) to pH 14 at20-25° C. Then the amino base product was extracted with toluene (933kg) at 43-47° C. by stirring for 15 min. The bulk was decanted during 15min at 43-47° C.; if necessary the pH was adjusted to >12 withadditional 30% NaOH, then the layers were separated. The organic layerwas washed with water (359 kg), then concentrated under vacuum (200-20mbar) at 45-50° C. to give the aminobase as an oily residue.

f) Preparation of

The aminobase from Step e was dissolved at 48° C. in toluene (825 kg)and the water content of the solution checked (KF<300 ppm). The toluenesolution was cooled to 1-5° C. and hydrogen chloride (gas, 45.1 kg) wasslowly introduced during ˜3 h through a canula at T_(max)=10° C. (gasintroduction is very exothermic). At the end of the addition, the bulkwas heated up to 97-103° C. and phosgene (166 kg) was slowly introduced(˜4 h) through a canula. At the end of the addition, the bulk was cooleddown to 80-84° C. and the reaction was checked by TLC. Additionalphosgene (16 kg) was introduced at 100° C., upon which the bulk turnedto a clear solution. After further stirring of the mixture 1 h at 100°C., the bulk was cooled to 80-84° C. The solution was concentrated undervacuum (250-50 mbar) at the same temperature to 770 L. The bulk waschecked for the absence of residual phosgene and the crude isocyanatesolution in toluene was cooled to 20-25° C., filtered through acartridge filter 0.3 micron.

Yield: Toluene solution of the isocyanate: 687 kg (34.7% a/a of productby GC), 234.4 kg product (100%, over Steps e and f).

g) Preparation of the title compound

A solution of the isocyanate from Step fin toluene (301 kg, ˜34%) wasadded in 30 min to a solution of the fluoramine (109 kg) from Step a intetrahydrofuran (948 kg) at 40° C. and the line washed withtetrahydrofuran (48 kg). The mixture was stirred for ˜3 h until completedissolution. Residual fluoramine was checked by TLC, and an additionalamount of the isocyanate solution (6 kg, ˜34% in toluene) was added andthe mixture stirred for 1 h at 40° C. and checked again by TLC. Thesolvent was removed by distillation under reduced pressure (300-20 mbar)at Tjacket=50° C. Ethanol (663 kg) was added to the residue at 25° C.and the mixture heated to 40-45° C. over 2.5 h and stirred at thistemperature for ˜2 h until complete dissolution.

Example 2 Preparation of Pimavanserin Hemi-Tartrate

A previously prepared solution of tartaric acid (41 kg) in ethanol (480kg) at 43° C. was added at 43° C. over 40 min to the ethanol solutionproduced in Example 1(g) and the line washed with 16 kg ethanol. Thesolution was cooled to 37° C. and seeded with pimavanserin Form C (0.5kg) and the product crystallized at ˜34° C. The suspension was stirredat this temperature for 30 min then cooled to 2° C. over 2.5 h andstirred for 2.5 h more at this temperature. The product was centrifuged(2 loadings) and the cake was washed with ethanol (3×15 kg/loading). Theobtained crude product was dried under vacuum (50 to 5 mbar) at 45° C.for about 49 h 20 min, sieved at 3 mm, and dried for another 5 h undervacuum. Yield of crude: 214 kg (86.0%).

Example 3 Preparation of Crystalline form A of PimavanserinHemi-Tartrate

The crude tartrate (212 kg) salt from Example 2 was heated in ethanol(948 kg) at 73-75° C. (reflux) for ˜1 h until dissolution. The hotmixture was filtered through a 0.3 μm cartridge filter, the line washedwith ethanol (30 kg) and the bulk heated to reflux for ˜0.5 h. Thesolution was cooled over ˜1 h to 49° C. and seeded with pimavanserin(0.4 kg) and the product crystallized at 48° C. The suspension wasstirred at this temperature for 30 min. The suspension was then cooledto −10° C. over ˜8 h and stirred at this temperature for an additional 8h. The product was centrifuged (2 loadings) and the cake washed withcold ethanol (3×21 kg/loading). The wet product was dried under vacuum(50 to 5 mbar) at 45° C. for 40.5 h. The resulting product was reworkedaccording to the procedure described below. Yield: 189 kg (89.2%)Rework:

Step #1: Free Basing of the Tartrate to Isolate Urea as a Solid

NaOH 30% (50 kg) was added over ˜15 min to a suspension of water (378kg), toluene (983 kg) and the tartrate salt (189 kg). The mixture washeated and stirred at 38° C. for 45 min, additional NaOH 30% (6 kg) wasadded for the pH to reach 12-14. The mixture was stirred at 38° C. for30 min until complete dissolution and the pH checked. Then, the reactionmixture was settled at 38° C., the layers were separated and the aqueouslayer was discarded. The organic layer was washed with water (378 kg) at38° C. and the toluene distilled at 45-50° C. under vacuum (200-80 mbar)to ˜380 L. Heptane (776 kg) was added to the distillation residue at 48°C. to crystallize the urea. The suspension was stirred at 50° C. for 30min, then cooled to 1° C. over ˜3 h and stirred at this temperature for1 h. The product was centrifuged (2 loadings) and the cake washed withcold heptane (2×27 kg/loading). The wet product (urea) was dried undervacuum (40 to 1 mbar) at 50° C. for about 12 h and sieved at 2 mm.Yield: 147 kg (91.5%)

Step #2: Re-Formation of the Tartrate by Addition of Tartaric Acid

The urea (147 kg) in ethanol (535 kg) was stirred at 40-45° C. untilcomplete dissolution, the solution filtered over a 0.3 μm cartridge andthe line washed with ethanol (59 kg). A solution of tartaric acid (26.3kg) in ethanol (223 kg) was added over 40 min through a 0.3 μm cartridgeto the solution of the urea (147 kg, from Step #1) in ethanol (594 kg)at 40-45° C., and the line and reactor washed with ethanol (19 kg). Theproduct crystallized during the introduction. The suspension was stirredat 43° C. for 30 min then cooled to −5° C. over ˜6 h and stirred at thistemperature for 2 h. The product was centrifuged (3 loadings) and thecake washed with cold ethanol (2×19 kg/loading). The wet product wasdried under vacuum (40-7 mbar) at 45° C. for about 34 h, sieved at 3 mm,and drying continued (20-7 mbar, 45° C.) for additional 6 h to producedry crystalline Form A. Yield: 167 kg (96.8%).

Example 4 Preparation of Crystalline form C of PimavanserinHemi-Tartrate

A suspension of crystalline Form A (167 kg) from Example 3 inpre-filtered and degassed methylethylketone (942 kg) was heated to 60°C. and stirred at this temperature for ˜2 h. The suspension was seededwith a suspension of crystalline Form C (5.6 kg) in methylethylketone(41 kg, filtered and degassed) and stirred at 60° C. for another 12 h. Asample was taken to check the complete conversion into Form C. Themixture was cooled down to 15° C. over 4.5 h and stirred at thistemperature for 2 h; then the product was centrifuged (2 loadings) andthe cake washed with cold methylethylketone (2×34 kg/loading). The wetproduct was dried for 1 h at 45° C., then under vacuum (500 mbar tomaximum over 5 h) at 45° C. for ˜18.5 h and the product sieved at 3 mmand packaged. Yield: 160 kg (95.8%).

Example 5 Recrystallization of Crystalline form A

Pimavanserin tartrate (3.04 kg) was slurried in ethanol (18.2 L). Theslurry was heated at 75° C. until it dissolved. The solution wasfiltered on a cartridge filter and the filter was rinsed with ethanol(0.9 L). The solution was cooled over 1 h to 55° C. and seeded withcrystalline Form A of pimavanserin tartrate (0.02 kg). The suspensionwas cooled to −10° C. in 3 h and stirred at this temperature for 2 h.The product was centrifuged and the cake was washed with cold ethanol(2×1.5 L). The wet cake was dried at 25-30° C. for 5 days to obtain 2.8kg of product (yield=92.4%).

It was discovered that the yield of manufacturing scale product wasimproved when the temperature of the suspension was decreased (e.g., toabout 10° C. or less, about 0° C. or less, or about −10° C. or less asin this example). Prior methods used a temperature of about 20° C. withlower yields (about 87%).

Example 6 Recrystallization of Crystalline Form C

A suspension of pimavanserin tartrate (8M) in pre-filtered and degassedmethyl ethyl ketone was heated to 60° C. and stirred for 8 h undernitrogen atmosphere. The mixture was cooled to 15° C. over 4.5 h andstirred for 2 h, then the product was centrifuged and the cake washedwith cold (15° C.) prefiltered and degassed methyl ethyl ketone. The wetproduct was dried for 15 h in vacuo at 45° C., discharged, packagedunder nitrogen and stocked at 0 to 4° C. By using an oxygen freeenvironment, oxidation of product was prevented and complete conversionto polymorph Form C was observed after 2 hours of stirring at 60° C.Yield 95.1%.

Additional methods for the preparation of pimavanserin, salts andcrystalline forms thereof, are found in U.S. Pat. Nos. 7,732,615;7,795,547; 7,790,899; 7,868,176 and 8,236,960, the entireties of whichare hereby incorporated by reference.

Example 7 Phase III Clinical Results in PDP Patients

A six-week, multi-center, randomized, double-blind, placebo-controlledstudy was conducted in PDP patients. The purpose of the study was toevaluate the safety and efficacy of 40 mg pimavanserin compared toplacebo in the treatment of PDP.

A total of 199 patients were enrolled in the study and randomized on aone-to-one basis to receive either 40 mg of pimavanserin or placebo oncedaily for six weeks, following a two-week screening period includingbrief psycho-social therapy. Patients also received stable doses oftheir existing anti-Parkinson's therapy throughout the study.

The trial was conducted on an outpatient basis with visits performed asfollows: Screening Visit 1, Day 1 (Baseline), Day 15, Day 29 and Day 43with a follow-up visit (Day 71) 4 weeks after the last regular studyvisit for those subjects who did not continue into an open-labelextension protocol. At the screening visit, a trained member of the sitestaff worked with the patient's caregiver to devise a structured plan ofsocial interaction for the patient and caregiver to follow at home. Thisbrief non-pharmacologic psychosocial counseling was intended to help thepatient and caregiver to manage the symptoms and provide standard ofcare prior to the blinded investigational treatment phase. Following thescreening visit, patients received two follow-up phone calls (˜3- and7-days from the screening visit) to review the plan and evaluateprogress. Only those patients who met entry criteria at baseline wererandomized to receive 40 mg pimavanserin or matching placebo for the6-week treatment period.

Each subject participated in the study during a screening period lastingup to 2 weeks, a 6-week investigational treatment period, and a 4-weekfollow-up period, for those subjects who do not continue onto anopen-label safety extension protocol. The maximum duration of the studyfor each subject was approximately 12 weeks. Pimavanserin wasadministered in tablet form, once daily by mouth in 40 mg doses (2tablets of 20 mg). Placebo was administered with visibly matchingtablets, using the same route and regimen. The safety of subjects wasassessed by monitoring adverse events, physical examinations, vitalsigns, clinical laboratory tests (hematology, clinical chemistry, andurinalysis), and electrocardiograms.

Brief Psycho-Social Therapy Period for PD Patients (BPST-PD)

The study included a modification to the screening period such thatpatients received up to 2 weeks of brief psycho-social therapy (BPST)designed as per current supportive care guidelines and modified for PDto aid the patient and caregiver in the management of psychotic symptomsprior to randomization. Patients who responded sufficiently to thisnon-pharmacologic social interaction therapy (i.e., who no longer meetstudy entry criteria), were not randomized into the blinded treatmentperiod. Patients who did not materially improve during this phase hadthe option of entering the treatment period early.

BPST-PD was used in this trial to reduce placebo responses in PDPpatients. BPST was developed for use in clinical trials of Alzheimer'spatients with behavioral disorders where placebo response rates oftenexceed 40%. It has been proposed that these high rates of placeboresponse result from a combination of Hawthorne effect and spontaneousremission. Hence many people may show improvement without activemedication and efficacy of pharmacologic treatments may be masked intherapeutic trials. The utility of BPST for the treatment of agitationin Alzheimer's disease (the CALM-AD trial) was recently reported inAmerican Journal of Geriatric Psychiatry (Ballard et al., 2009). In theCALM-AD study, BPST treatment achieved a 6-point reduction on theCohen-Mansfield Agitation Inventory. In addition, significant reductionsin agitation have been reported in 2 other randomized controlled trials(Cohen-Mansfield et al., 1997 and Cohen-Mansfield et al., 2007).

BPST-PD non-pharmacologic therapy was administered over the 2-weekscreening period by a trained site staff member working with the PDpatient's principle caregiver to train and implement the therapy athome. The treatment is simple and clinically applicable, comprising aseries of social interactions between the caregiver and patient based ona plan designed specifically for them. The trained site staff memberinteracts with the caregiver at the screening visit to explain theBPST-PD and mutually develop the social interaction plan for thepatient/carer dyad. The site staff member then followed up by phone orin person at 3-7 day intervals during the 2-week screening period toreview the plan and monitor implementation.

Exemplary 2-Week Screening Period Protocol

BPST-PD entails daily 10-30 minute semi-structured interactions betweenthe patient and caregiver. These interactions may be incorporated intotime already dedicated to caretaking such as while bathing, feeding andotherwise caring for the patient. The caregiver will require trainingand assistance from site staff in developing and implementing anindividually-designed interaction strategy for the patient involved.There will be a total of 4 visits (2 at the clinic and 2 by phone), asfollows, between the site staff and the caregiver during the 2-weekscreening period leading up to baseline/randomization. The purpose ofeach visit is summarized below:

Screening Visit 1 (SV1): BPST-PD training of the caregiver occurs in theclinic at this first study visit. This session is specifically designedto help understand each patient and design a plan of interaction. Thissession will last approximately 30 minutes. The following suggestedscript (indented paragraphs below) is intended to guide site staff inthe initial caregiver interview such that an individualized interventionplan for the patient and caregiver can be devised:

The goals of this BPST session are:

-   (i) to help you, the caregiver, to complete an assessment of the    person with PDP. We will be interested in details about the    patient's past history, personal experiences, and current behaviors.-   (ii) based on this assessment, we will work together to devise an    intervention plan specific for the patient and you.-   Overview: This 30-minute training session will be followed by 3    additional follow up visits (conducted either by phone or in person)    to support you during implementation of the intervention plan. The    intervention entails daily one-to-one social interactions between    you and the patient during the 2-week screening period. These    interactions may be as simple as a conversation or other shared    activity selected from the list below. It is important that the time    spent with the patient is dedicated and undisturbed and therefore,    to the extent possible, any radio and television should be turned    off and any other interruptions minimized while the social    interaction takes place. The activity should continue for at least    10-30 minutes and for as long as the patient wishes to continue    participation. The intervention should be personalized to the    patient based upon the assessment of “background features”.-   Initiation of one to one communication: To initiate the interaction    a statement such as “I thought it would be nice to have a chat or do    something together. Would you like that?” should be made. If the    patient chooses to engage in a chat, a conversation could be    initiated using a prompt regarding the person's past life. Examples    might be: Do you remember when we . . . ? . . . Didn't we . . . ?.”    Or similar prompts related to past hobbies, previous places of    residence or other topics relevant to the patient. The use of a    photo album or other appropriate materials to prompt the discussion    may be useful.-   If a person declines the interaction his/her wishes should be    respected. A further attempt to initiate the activity could be made    at a later time. The offer of a cup of tea or coffee may act to    normalize the social interaction and increase the motivation of the    person to participate.-   Activities for one to one interactions: The nature of the activities    undertaken will depend on the ability of the person with PDP—see    below (a to c).-   The first activities (a & b) require a more active involvement from    the patient compared to the latter activity (c). We will help you    will select the most appropriate interactions to try with the    person. The selection will depend on the person's impairment and    personal likes and dislikes. It may be that more than one activity    is selected. If the caregiver has ideas for other structured    activities that the patient might enjoy, these may be considered.    Activities:-   (a) Manual and mental activities, such as making/doing a simple    jigsaw or crossword puzzle. Remind the caregiver that they can    function as the patient's hands if Parkinson's symptoms are too    severe.-   (b) Physical based activity such as taking a walk, gardening,    setting tables, washing up. This may also help the person feel more    included and help them to have fun and enjoy the activity.-   (c) Reading to the person from a favorite book, magazine, or    newspaper.-   A “box of activities” (including games, photographs, favorite books    and music, etc.) could be prepared to help you.    Different Topics of Conversation or Activities:-   As the shared activity is intended to take place daily over the    intervention period, it will probably be necessary to have some    variations for the conversation or activity as it may otherwise    become boring or repetitive. As far as possible, however, the    “variations” should follow the same themes. It is important to keep    the therapy simple and focused or there will be a significant    detrimental impact on compliance.    Examples may be:-   If the interaction is a conversation about vacations, photographs    and other reminiscence objects could be drawn together related to    several different vacations, enabling the conversation to focus on    different vacations on different days.-   If the selected activity is a jigsaw, depending n the complexity of    the jigsaw—several different puzzles could be used over the two week    period. In the event that the jigsaw links to particular episodes in    the patient's life, reminiscence objects or conversation prompts    could be identified, as appropriate.-   Shall we go through the ‘Assessment Worksheet’ so that we can    determine which of these activities would be most appropriate for    the patient? [Now complete Assessment Sheet below]    [End of Script]

Assessment Sheet: below is an exemplary assessment sheet that may beused as described above:

ASSESSMENT SHEET (To be completed by the trainer during the initialtraining session) Please provide details about the relevant materialunder each of these headings. The goal is to focus on things that: 1)May be important with respect to psychosis and related behaviors, and 2)Will help refine the social interaction intervention. Psychological andsocial factors: Relevant details about the person's history of PD andpsychotic symptoms, their coping style, pre-morbid personality, andsocial situation. The following may be relevant questions: • Is there aspecific time of day that the psychotic symptoms occur? • How agitateddoes the patient become during these episodes? • What's the patient'spersonality like? Has the patient's PD and/or psychosis affected theirpersonality? How? • What does the patient like to do? What are his/herhobbies? Have the patient's interests/hobbies changed because of theirPD and/or psychosis? • When the patient is experiencing psychosis, howdoes the patient cope? How does the caregiver cope? • Are there otherfamily members or friends that interact with the patient routinely? Dothey see the patient during episodes of psychosis? How do they cope? •Are there particular social triggers for the onset of psychoticsymptoms? Are there practical things that can be done to prevent thetriggers? Environmental factors: Relevant details about the person'scurrent living environment and ability to cope with and enjoy thissetting. The following may be relevant questions: • Where does thepatient live? (House, apartment, with extended family, assisted living,etc . . .) • Is there a particular place where the patient experiencespsychotic symptoms (indoors/outdoors, bedroom, living room etc.) • Isthere anything about the environment that worsens or improves thepatient's condition? • Are there particular environmental triggers forthe onset of psychotic symptoms? Are there practical things that can bedone to prevent the triggers? Physical factors: Relevant details aboutthe person's physical condition. The following may be relevantquestions: • Are there particular physical limitations that would impedethe patient's ability to interact for the purposes of the BPST? • Arethere particular physical symptoms of Parkinson's disease that worsen ortrigger psychosis for the patient?

Documentation of Plan: Once selected, the intervention plan should besummarized in writing (about 1-page) and include details of the selectedactivity(ies) to be carried out daily in the one-to-one interactionsbetween the patient and caregiver. It should also prospectively definethe expected time and duration of each interaction period. If more thanone conversational topic or activity is to be used, it is very importantthat they are defined carefully in the therapy plan, where possibledefining which day each theme will be used. The caregiver should begiven a copy of the plan with a second copy retained by the trainer(site staff). The caregiver should be asked to keep a brief diary ofeach session.

Screening Visit 2 (SV2): BPST-PD follow-up phone contact occursapproximately 3-4 days after SV1 and should last approximately 15minutes. The caregiver is contacted to assess how the implementation isgoing and to provide supportive suggestions for any identified concerns.It should begin with a review of the diary notes of the caregiver. Theaim is to re-emphasize key points of the interaction plan. The generalapproach should be to start by praising any positives: attempts toundertake any intervention, completed interventions, any positive impactupon the person with dementia that is achieved, any pleasure that thecaregiver derived from the intervention and any flexible problem solvingthat the caregiver used to manage, change, and/or implement theintervention. If the intervention has not been implemented, the reasonsfor this should be elicited. If the caregiver encountered problems withand was unable to implement the intervention effectively, solutionsshould be proposed. Examples may be:

-   -   Caregiver has not understood the intervention: the approach can        be re-explained, and then the caregiver asked to explain it        themselves in their own words.    -   Insufficient time to deliver intervention: the reasons can be        explored, the times of the intervention can be modified to ones        that are more convenient, strategies for eliciting help to cover        other conflicting commitments can be explored; sharing of the        intervention between caregivers can be explored.    -   Failure of engagement: if the patient has been unwilling to take        part in the intervention, minor changes to the plan or approach        may be helpful. For example, to present the intervention at a        time of day or for a duration that may be more acceptable to the        patient.

There may be a need to make minor adjustments to the intervention basedupon a re-formulation of the behavior and the difficulties withimplementing the intervention. This may for example incorporate aslightly different strategy for avoiding a trigger, a change of music oremphasis on a different approach within the selection of activitiesincluded within the interaction intervention.

Screening Visit 3 (SV3): BPST-PD Follow-up phone contact occursapproximately 1 week after SV1 or 3-4 days after SV2 and should lastapproximately 15 minutes. Activities for this visit should include thesame review of the caregiver's diary and activities as in SV2 withcontinued in-person support of the caregiver. Strategies for managingany challenges and improving engagement with the patient should bediscussed, as needed. The trainer will again contact the caregiver toassess how the implementation is going and to provide supportivesuggestions for any identified concerns.

Screening Visit 4 (SV4=Baseline visit): This visit occurs on site at theconclusion of the screening period (approximately 2 weeks after SV1) andis intended to provide closure of the BPST-PD intervention. The emphasisshould be on re-enforcing any positives that have come from theintervention. Explain clearly that that the use of BPST may now bediscontinued. Explain that a different member of the study team willevaluate the patient to determine if they meet the criteria necessaryfor moving on to the pharmacological aspect of the study and that thecaregiver will be informed of the outcome. Should the patient continueinto the active treatment phase, the caregiver's continued support andknowledge of the patient will be important.

The use of BPST-PD may reveal patients who benefit from psycho-socialtherapy alone, and thereby reduce placebo response in theinvestigational treatment phase of the clinical study by pulling thatresponse forward of baseline measures. The use of BPST-PD limitsrandomization only to those patients for whom pharmacologic treatment isappropriate. It may have the added advantage of encouraginginvestigators who may be reluctant to enroll their more severe patients(i.e., those in need of urgent non-placebo intervention) by offering thepatient and caregiver non-pharmacologic psycho-social therapy to helpmanage symptoms through at least the 2-week treatment period. For thosepatients who respond to this supportive care, benefit may extend beyondthe screening period.

Clinical Study Inclusion Criteria:

-   -   i. Male or female of 40 years of age or older with a clinical        diagnosis of idiopathic Parkinson's disease with a minimum        duration of 1 year, defined as the presence of at least three of        the following cardinal features, in the absence of alternative        explanations or atypical features: rest tremor, rigidity,        bradykinesia and/or akinesia, postural and gait abnormalities.    -   ii. Female subjects must be of non-childbearing potential        (defined as either surgically sterilized or at least 1 year        post-menopausal) or must agree to use a clinically acceptable        method of contraception (such as intrauterine device (IUD),        diaphragm, or oral, injectable (e.g. Depo-Provera) or        implantable contraception (e.g. Norplant System), for at least        one month prior to randomization, during the study, and one        month following completion of the study.    -   iii. Subjects must have psychotic symptoms that developed after        the diagnosis of Parkinson's disease was established. These        symptoms must include visual hallucinations and/or auditory        hallucinations, and/or delusions.    -   iv. Psychotic symptoms must have been present for at least one        month and the subject must have actively experienced psychotic        symptoms each week during the month prior to the Screening        visit.    -   v. Symptoms severe enough to warrant treatment with an        antipsychotic agent; documented at screening by items A and B of        the NPI, and defined as a score of 4 or greater on either the        Hallucinations (Frequency×Severity) or Delusions        (Frequency×Severity) scales OR a total combined score of 6 or        greater.    -   vi. At the baseline visit, subject must have a SAPS        Hallucinations or Delusions global item (H7 or D13) score ≧3 AND        a score ≧3 on at least one other non-global item using the        modified 9-item SAPS Hallucinations and Delusions domains.    -   vii. Subject must have clear sensorium at study entry (i.e.,        oriented to time, person, and place).    -   viii. Subjects that are on anti-Parkinson's medication must be        on a stable regimen/dose for 1 month prior to Day 1 (Baseline)        and during the trial.    -   ix. Subject that has received stereotaxic surgery for        subthalamic nucleus deep brain stimulation must be at least 6        months post surgery and the stimulator settings must have been        stable for at least 1 month prior to Day 1 (Baseline) and must        remain stable during the trial.    -   x. The subject is willing and able to provide consent.    -   xi. Caregiver is willing and able to provide consent and agrees        to accompany the subject to all visits.    -   xii. Subject and caregiver are willing and able to adequately        communicate in English for the purposes of the primary endpoint        assessments by the MedAvante remote raters.

Primary Clinical Endpoint: The combined score for the modified 9-itemhallucinations and delusions domains of the Scale for the Assessment ofPositive Symptoms (SAPS-PD). The nine items from the hallucinations anddelusions domain of the SAPS scale have been shown to be particularlyrelevant to the expression of psychotic symptoms in patients withParkinson's disease and have high inter-rater reliability for assessmentof severity.

Key Secondary Endpoint: Parts II-III of the Unified Parkinson's DiseaseRating Scale (UPDRS), which measures motor function. The objective ofthis secondary endpoint was to demonstrate that pimavanserin couldachieve its antipsychotic effects without worsening motor function ascompared placebo in PDP patients.

Other Secondary Endpoints: Changes in the Clinical Global ImpressionScale (CGI) with emphasis on severity (CGI-S) and improvement (CGI-I) ofpsychosis.

Exploratory Endpoints: the Caregiver Burden Scale, and Scales forOutcomes in Parkinson's Disease-Sleep scale (SCOPA-Sleep).

Summary of Results:

-   -   Pimavanserin met the primary endpoint by demonstrating highly        significant antipsychotic efficacy as measured using the 9-item        SAPS-PD scale (p=0.001).    -   These results were further supported by a highly significant        improvement in the secondary efficacy measure, the CGI-I scale        (p=0.001).    -   Pimavanserin met the key secondary endpoint for motoric        tolerability as measured using Parts II and III of the UPDRS.        Pimavanserin conferred antipsychotic activity while maintaining        motor control.    -   Clinical benefits were observed in all exploratory efficacy        measures with significant improvements in nighttime sleep,        daytime wakefulness, and caregiver burden.    -   Pimavanserin was safe and well-tolerated in the trial.

Primary Endpoint Results: SAPS-PD assessments were performed by blinded,independent centralized raters. The pimavanserin arm of the studydemonstrated a robust 5.79 point improvement in psychosis at day 43compared to a 2.73 point improvement for placebo, representing a highlysignificant and clinically meaningful treatment difference of 3.06points on SAPS-PD (p=0.001).

Baseline Mean Placebo Pimavanserin Mean Change at Day 43 (n = 90) (n =95) Placebo Pimavanserin P-value SAPS-PD 14.73 15.88 −2.73 −5.79 0.001Note: mixed model repeated measures (MMRM) method was applied in primaryanalysis of the intent-to-treat (ITT) population. The significance testwas based on least-square mean change from baseline for each arm using a2-sided beta=0.05.

Key Secondary Endpoint Results: A pre-specified, non-inferiorityanalysis was used to compare the mean change from baseline to day 43 forpimavanserin versus placebo using a two-sided 95 percent confidenceinterval (CI) for the treatment difference. Moteric improvements wereseen in both the pimavanserin and placebo arms and the CI associatedwith the treatment difference did not exceed a pre-specified margin of 5points for clinically relevant change, confirming that pimavanserin metthis key secondary endpoint and did not worsen motor function in PDPpatients. Both the pimavanserin and placebo arms showed improvements incombined UPDRS II & III scores (−1.69 for placebo, −1.40 forpimavanserin).

Sleep Improvements: the SCOPA-sleep scale was used to evaluate nighttimesleep and daytime wakefulness in Parkinson's patients. Pimavanserindemonstrated significant improvements on both nighttime sleep (p=0.045)and daytime wakefulness (p=0.012) on SCOPA.

Caregiver Burden: the Caregiver Burden Scale was completed by thecaregiver to provide a quantitative assessment of burden associated withthe patient's functional/behavioral impairments, the circumstances ofat-home care, as well as the caregiver's health, social life andinterpersonal relations. Pimavanserin demonstrated a highly significantimprovement on the Caregiver Burden Scale (p=0.002).

Safety and Tolerability Profile: pimavanserin was safe and welltolerated in this trial. The most common adverse events were urinarytract infection (11.7% placebo vs. 13.5% pimavanserin) and falls (8.5%placebo vs. 10.6% pimavanserin). The only serious adverse events thatoccurred in more than one patient were urinary tract infection (1placebo vs. 3 pimavanserin) and psychotic disorder (zero placebo vs. 2pimavanserin). Only 5 other adverse events occurred with an incidencegreater than or equal to 5% in either arm (peripheral edema,hallucination, confused state, nausea and headache). Adverse events weregenerally characterized as mild to moderate in nature. Ninety percent ofthe patients who completed the clinical phase of this trial elected toroll over into the ongoing open-label safety extension study. Patientswere only eligible to participate in the extension study if the treatinginvestigator also deemed them to be likely to benefit from continuedtreatment with pimavanserin.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A method for excluding from a clinical studypatients with likelihood for placebo response, the method comprisingscreening a group of psychosis patients by administering socialinteraction therapy designed for psychosis, wherein patients who respondsufficiently to the social interaction therapy are excluded from asubsequent clinical study.
 2. The method according to claim 1, whereinthe social interaction therapy is administered one day to two weeks. 3.The method according to claim 1, wherein the social interaction therapyis a brief psycho-social therapy.
 4. The method according to claim 1,wherein the patients are Parkinson's disease psychosis patients.
 5. Themethod according to claim 1, wherein the social interaction therapy is anon-pharmaceutical therapy.
 6. The method according to claim 1, whereinthe method is integrated in a clinical trial for psychosis patients. 7.The method according to claim 6, wherein the psychosis patients areParkinson's disease psychosis patients.
 8. A method for improvement ofdaytime wakefulness in a Parkinson's disease patient, comprising theoral administration of pimavanserin, or a pharmaceutically acceptablesalt thereof, to the patient in a daily dose of about 40 mg, wherein theimprovement of wakefulness is measured on the Scales for Outcomes inParkinson's Disease—Sleep scale.
 9. The method according to claim 8,wherein the improvement of daytime wakefulness is more than 20% comparedto baseline after oral administration of pimavanserin, or apharmaceutically acceptable salt, after 43 days.
 10. The methodaccording to claim 8, wherein the improvement of daytime wakefulness isabout 29% compared to baseline after oral administration ofpimavanserin, or a pharmaceutically acceptable salt, after 43 days.